Expert Critique

There are a multitude of factors to consider when choosing the best diabetes drug for a patient, and in 2008 the FDA added an additional layer of complexity when it published a Guidance for Industry stating that all new antidiabetic therapies must establish cardiovascular safety. This was in response both to the potential cardiovascular risk of existing medications (i.e rosiglitazone) as well as to the elevated risk of cardiovascular disease in this patient population (the leading cause of morbidity and mortality). As detailed in the article below, the verdict is still out as to what extent this new requirement has benefited the diabetes population.

On the one hand, trials such as EMPA-REG and LEADER, which showed positive cardiovascular outcomes independent of glycemic control, may end up benefiting the cardiovascular population at large through the insight gained on the underlying mechanisms and their potential use as cardiovascular drugs. On the other hand, while the relative rates of benefit in these trials sound impressive, a second look can reveal that the absolute number needed to treat is rather high when compared to the extremely high cost of such new agents, which are not always covered by insurance. Further, one of the physicians interviewed in the article points to the fact that perhaps our limited healthcare funding resources should be funneled toward preventive efforts as opposed to intervening on complications, though in view of the growing epidemics of obesity and diabetes in this country and worldwide, this view may unfortunately be too idealistic.

Full Critique

In 2008, motivated by the high prevalence of cardiovascular disease in diabetes and controversy about the outcomes of drugs like rosiglitazone (Avandia), the FDA issued a Guidance for Industry that all new drugs developed to manage glycemia in type 2 diabetes needed to demonstrate cardiovascular safety.

As a result, all new antidiabetic agents approved since then have had dedicated trials to look at a composite endpoint of major adverse cardiac events -- cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke -- in type 2 diabetes patients with high cardiovascular risk.

"Historically, the approval of diabetes drugs was based on improvements on reductions in fasting glucose or in [hemoglobin] A1c," said Robert Eckel, MD, of the University of Colorado School of Medicine and a past president of the American Heart Association. "The 2008 FDA guidance was a kind of pushback for glucose-lowering therapy."

Initially, some members of the diabetes community were not pleased with the idea of putting drug companies through the expense and time of phase III trials for cardiovascular safety, Eckel noted.

"But now that we've looked back," he said, "we've learned some things that maybe were a bit surprising."

'An explosion of scientific information'

"Since the 2008 FDA Guidance, there has been an explosion of scientific information about drugs to treat diabetes," said Steve Nissen, chairman of cardiovascular medicine at the Cleveland Clinic.

"We learned that empagliflozin, liraglutide, and semaglutide all reduce cardiovascular morbidity and mortality," he explained. "We learned that DPP-4 (dipeptidyl peptidase-4) inhibitors provide no meaningful benefits and that saxagliptin increases heart failure. We discovered that canagliflozin reduces cardiovascular events, but increases risk of amputations. We learned that extended-release exenatide and lixesenatide do not reduce cardiovascular morbidity or mortality."

In 2015, the EMPA-REG trial showed that the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (Jardiance) reduced the relative risk of major adverse cardiac events in high-risk diabetes patients by 14%, compared to a placebo group getting usual care. Last year, the LEADER trial showed that the glucagon-like peptide-1 (GLP-1) drug liraglutide (Victoza) reduced major cardiac events by 13%. More recently, the SUSTAIN-6 study showed that semaglutide, a novel GLP-1 drug, reduced the risk of major adverse cardiovascular events by a relative 26%.

"None of these insights would have occurred without rigorous randomized controlled outcome trials," Nissen stated.

Are the trials worth it?

"Categorically, absolutely, yes; the trials are worth it," said Hertzel Gerstein, MD, of McMaster University in Hamilton, Ontario.

"The diabetes community and our patients have been well-served by these outcome trials," he noted. "They've helped us to generate new paradigms and new ways of thinking about these drugs -- specifically, the SLG2 inhibitors, which are now being thought of very differently as the result of the outcome trials and are being tested as cardiovascular drugs."

Just because every trial does not yield a positive result doesn't mean it's a useless trial, he added. "A lot of really important information has come from trials that have shown neutral cardiovascular effects," he said.

But, nearly 9 years after the trials first started, not everyone sees their value. Some physicians think the study design should be changed -- the trials should be longer, or should include patients without cardiovascular disease, or should study the effects of new diabetes agents on retinopathy, neuropathy, or nephropathy.

Others maintain that the overall premise of the trials is not correct.

"I believe that the amount spent on these trials could be spent in better ways," said Joel Zonszein, MD, of the Albert Einstein College of Medicine in New York. "In my book, we should use that money in trials to prevent complications and to treat diabetes early in the disease."

"Approximately 130,500 people will be studied in these trials -- patients who are elderly and very sick with cardiovascular disease," he continued. "We are spending lot of money not to prevent complications, but to treat them."

One thing the trials have shown is the value in treating diabetes populations differently. "If I have a patient in the hospital with congestive heart failure who also has uncontrolled diabetes, I'd recommend we put the patient on SLGT2, if no contraindications and if covered by the insurance -- which often is a problem," Zonszein noted.

"But I am convinced that in this country, and all over the world, what we mainly are doing is chasing A1cs," he said. "We don't treat patients aggressively early in the disease to prevent complications and we spend a lot of money treating complications, which are the major cost of the disease."

Newer, safer drugs

"A handful of critics predicted that requiring clinical trials would impede the development of new drugs," said Nissen. "In fact, the opposite has occurred. The guidance has actually accelerated drug development."

"We have learned more about diabetes drugs in the last 9 years than in the previous 4 decades," he added.

Most importantly, Eckel noted, cardiovascular safety has been established for every compound that has gone through the studies. "Most people agree now that the safety net has been assured," he said. "There's no evidence of harm from these agents."

That assurance has helped him and other doctors change their minds about the trials over time.

"My initial feeling was negative because of the importance of glucose-lowering, mostly for microvascular complications," Eckel explained. "But now, I'm more in favor of sustaining this requirement because of the important information we are learning from it."

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